CA1324133C - N-(4-piperidinyl) bicyclic condensed 2-imidazolamine derivatives - Google Patents

Abstract

ABSTRACT
Novel N-(4-piperidinyl)bicyclic condensed 2-imidazolamine derivatives Novel N-(4-piperidinyl)bicyclic condensed 2-imidazolamine derivatives and their pharmaceutically acceptable acid addition salts having anti-histaminic properties, compositions containing the same, and methods of treating allergic diseases in warm-blooded animals.
The novel derivatives of the general formula

Description

132~133 130Sf JAB 559 19 :

::
~ov~ (4-piperidinyl) bicyclic condersed 2-imidazolamine ~rivati~es ;;

".
~ ,~

Ba~ik~r~u~ of ~h Q ~Y=~aQ~ ; ;
In ths ~.S. Patiant ~b. 4~219,559 thar~ ar~ ae3cribed a numb~r o~
l-sub3tituted ~-heterocyclyl-4-piperidinamia~s as compounds havîng ~: 25 usa~ul anti-histami~ic prop~rties.
rth~ series of N-heterocyclyl-4-piperidinamin~s as compou~ds I hav;ng us~ful a~ti-histami~ic and s~rotonin antagonistic prop~rti~s have f : : been d~scribed in U.S. Patent Nos. 4,S56,6~0, 4,634,704, 4,695,569 a~d f~ 9,588,722. :
~; 30 Tbe compounds of tbe present i~vencion are substit~t~d i~ a 3~ pr~iously undisclos~d manner and show ~avourabl~ phiarmacological pr~p~rtie~s.

35~

1 32~ ~ 33 Descript;o~ o~ th~ invention:

R Alk-R
L-R~R ~ ~ ~` A (I), th~ pharm~o~utically acceptable acid-addition salts and possibl~
stsreochemically isomerio forms thereof, wherein:
A =A -A3-A is a bivalent r~dical having the for~ul~
-C~=C~-C~=CH- ta-13, -~=C~-C~=C~- (a~2), -C~ C~=C~- ~a-3~, 15 -C~=CH-~=CX- (a-4), or -CH=CH-C~=E7- ~a-5~
wh~rein on~ or two hydrog~n a~oms in said radicals (a-1)-(a-5~ ~ay, indep~ndent:Ly ~rom each other, be replaced by halo, Cl 6alkyl, C1 6alkylo~y, trirluoromethyl or hydro~y~ ~
1 20 ~ i~ h.~droge~ or Cl 6alkyl; -I R i3 uranyl s~bstitut~d ~ith C1 6al~yl, pyrazinyl, thla~olyl, ~::
or i~ldazolyl option~lly sub~tituted wri~h Cl 6al~yl;
Y g~ Cl_6alkyl~ C3-6a~loal~yl~ ~r -Cl 6alk I o~ (C1 6~1kyl)~C~: 3 L i~ C3 6alken~1 optionally sub5t Ltuted with Ar , or L i a radical of formula ~AlX-R (b~
-Alk-0-R (b-2), -~lk-~ 5)-R6 (b-33 I ~ 7 ~ 30 ~lk-Z-C(=0~-R (b-4), or : -c~2-cB~oH)-~2-o-R (b-5);
~R3 is hydrogen, Ar -thio, Ar3-sulfon~l, 4,5-dihydro-5-oxo~
l~ ;: tetrazol-1-yl being optionally substituted ;n its 4-po~ition with Ar or Cl 6al~y~, 2,3-dihydro-1,4-b~nzodioxin-2-yl, 2,3-dihydro 1,4-benzo-dio~in-~-yl, 4-morpholi~yl, 1-piperidinyl or l~pyrrolidinyl, or when l ~ ~
;~ " ' :, . ~

.
i : :

R is furanyl substitut~d with Cl 6alkyl ard A _A -A =~ is a bivalent radical of formula (a-1) or (a-2), R may also be A~ , 2,3-dihydro-2-o~o-1~-benzimidazol-1-yl or 1-~C1 6alkyl)pyrrolyl;
R is Cl 6alkyl or Ar , 2 R is Cl 6alkyl optionally substituted with Ar ;
~ is Ar or C1 6alkyl optionally substituted with Ar or when A =A -A =A is a radical of formula (a-1) or (a-2), R may also be l~-benzimidazol-2-yl;
R is C1 ~alkyl, Ar -C1 6alkyl, Ar , amino, Ar -amino, mono-and di~Cl 6alkyl)~mino, mono- and di(Ar -Cl 6alkyl)amino, l-pipe~idinyl, 1-py~rolidinyl, 4-morpholinyl, C3 6cycloalkyloxy, Cl 6alkylo~y or Ar -el 6alkylo~y;
' Z i8 O, ~R~ or a direct bond; said R~ boing hydrog2n or j C1 salkyl optio~ally substitutad with Ar ;
I 15 R is Ar :
ach Alk i~dependently being C1 6alkanediyl;
Ar is phenyl, 3u~stituted phenyl, naph~halenyl, thienyl, ¦ halothi~nyl, Cl 6alkyl substituted thienyl or furanyl, wh0rein ~aid substituted phenyl is phenyl substituted with 1, 2 or 3 sub~titu~nts, ¦ 20 each indcpenden~ly 3elect~d from the group consi~ting of halo, hydro~y, : :
~itro, cyano, ~rifluoromethyl, C1 6alkyl, C1 6alkylo~y, Cl 6al~yl~hio, ~ :
mercapto, C~ 6~1~kylsulfonyl, C1 6alkyl~ulfonylC1 6alk~1, ph~nyl-; C1 0al~yl~ulfonyl, phe~ylsulfonylC~ 6ialkyl, ami~o, mo~o- and di(Cl ~alkyl)amino, carbo~yl, Cl 6alkylo~ycarbonyl and Cl 6alkylcarbo~yl: -. 25 Rr has tha ~ame meanings of Arl, and may ~lso be pyridinyl, mono-and di(Cl 6al~yloxy)pyr;dinyl or furanyl substituted with C1 6alkylJ a~d .:
Ar has the same meanings of Ar , and may also be pyrazinyl, l-(C1 6alkyl)p~rrolyl, thiazolyl or imidazolyl optionally subst;tuted with Cl 6alkyl, provided that ~ YA -A =A is a radical of formula ~a-13 or (a-2) when L i~ a radical of formula (b-4).

As used in the foregoing definitions the term halo is generic to ~luoro, chloro, bromo and iodo, the term "C1 5alkyl" is meant to include straight and branchod ~aturated hydrocarbon radicals, having ..,:
;,'.
~ ~ ....
:j .' ::
`-!

from 1 to 6 carbon atoms, sueh as, for e~ample, methyl, ethyl, l-methyl~
ethyl, l,l-dimethylethyl, propyl, bukyl, pentyl, he~yl and the liXe: the term "C3 6cycloalXyl" is generic to cyclopropyl, cyclobutyl, cyclo-pentyl and cyclohexyl; the term "C3 6alkenyl" is meant tG include straight and branch chained hydrocarbon ra~icals containinq ~ne double bond and having from 3 to 6 carbon atoms such as, for example, 3-propenyl, 2-butenyl and the like, and when a C3 6alkenyl is substituted on a heteroatom, the~ the carbon atom of said C3 6alkenyl connected to said heteroatom preferably is saturated.

The compound~ of formula ~I) m y also e~ist in hydrated or in solvent addition forms a~d said form3 are inte~d~d to be included within the scope of the presen~ ention.

An inter~sting subgroup among the compounds of formula (I) co~prises tho~ compou~ds of formula (I~ wher~in A =A -A3=A4 i~ a bivalent radi¢al hav;ng the formula ~a-l). ~nother interesti~g subgroup among the compound~ of formula lI) comprises thos~ co~npound~ o~ ormula (I3 wherein A _A -A ~A is a bivalent radical having a formula ~a-2 through (a-5), ~ith (a-23 being the mc\st interesting subgroup.

I Preferr0d compounds within th~ r~tiou ar~ those compounds of orm~1~ (I) wher01n R iæ hydrogen and R is hyd~ogen or Cl 6al~yl.
Parti~ularly prefsrred compounda ~ thin tho inventio~ are thos0 pre~rred compounds of formula (I~ wh~rein L is C3 6al~enyl optionally substitut~d ~ith phenyl or substituted phe~yl, or wher~in L is a radical of formula ~b~ b-2), ~b 4) or ~b-5) wherein R is as defined hereinabovP, R is Cl 6alkyl, phenyl or substituted ph~nyl, R is phenyl, ~ubstituted phenyl or C~_6alXyl optionally substitut~d w~th phenyl ar substituted ph~nyl, ~ i~ hydrogeu or Cl 6alXyl, and R
i~ ph~yl, sub~titut2d ph~nyl or ~aphthalenyl.
I More par~icularly pre~erred compounds within the invention are those ¦ particularly preferred compounds of for~ula ~I) wher2in L is a radical of formula ~b~l) or (b 2) wherein R is hydrogen, phenylsulfonyl, 4,5-dihydro-5-oxo~ tetrazol-1-yl being optionally substituted in its ,~ ~ , ' .
: ::
~ ':
,1 '', `I . -.

4-position with Cl ~alkyl, 2,3-dihydro-1,4-benzodio~in-2-yl, 4 morpholinyl, l-piperidinyl or 1-pyrrolîdinyl, or when R is furanyl substituted with Cl 6alkyl and A =A -A =A is a bivalent radical of formula (a-1) or (a-~), R may also be 2,3-dihydro-2-oxo-lH-benzimidaz~l-1-yl, thienyl, furanyl, phenyl or substituted ph~nyl.
Especially preferred compounds ~ithin the invention are those more particularly preferred compounds of formula (I) wherein A =A -A =A is a bivalent radical of formula (~-1) or (a-2) and L is a radical of formula (b-l) wherein R is hydrogen or phenyl optionally substituted with halo, C1 4alkyl, C1 4alkyloxy or hydroxy~
A parti~ular suhgroup of compounfls of formula ~I) compri~es those compounds, pref0rred, particularly pr~f~rrad, rnore particul~rly pr~ferred or ~spec;ally preferra~ compounds wherein R is furanyl substituted with C1 6alkyl.
A moro particular subgroup of compounds of formula (I) comprises thoso compounds, preferred~ p~rticularly pre~erred, more particularly preferred or e~pecially pref2rred compounds o~ formula (I) wh~rein ~ :
, -Alk-~ ~s C1 4alkyl-5-C1 4alkyl-2-fU~a~Yl~ ~1 4alkYl~4~Cl-4alkYl~2~
j furari~l, Cl ~alkyl-3-Cl ~al~yl-2-furanyl, Cl ~alkyl-2-C1 4al~yl-3-furanyl, Cl 4al~yl-4-Cl ~lkyl-3-~ura~yl or Cl 4alkyl-5-C1 4al~yl-3-~uranyl.
Tha most pr~ferred compour,ds ~ithin the in~ention are sslected ~rom ~-th~ group con~ ing of 3-e(S-m0thyl-2-~uranyl)methyl]~ 1-methyl-4-pip~ridinyl)-3 -imidazo~4,5-b]pyridin-2-ami~, th~ pharmac utically , 25 acceptable acid ~ddition salts and the st~r~oche~ically isomeric forms thar~ofO
~! In order to simplify the structural representations of the compou~ds :
' o formula (I~ and of certain prec~rsors and intermediates thereof the ~ :
f R Al~-Rl 1 30 ~ ~ A2 ~adical will herea~t2r be i l2 ~ ~ 4,lA3 represented by the symbol D.
A
I The compounds of ~ormula (I) are g0n0rally prepar0d by N-~lkylating i 35 a piperidine of formula (II) with a reagent oE formula (III).

~-alkylation L-Wl I ~-D ~ L-D (I) ~III) (II) reaction In formula ~III) and in a number of the following intsrmediates W and W represent an appropriate leaving group such as, for example, halo, preferably, chlo~o, bromo or iodo, or a sulfonyloxy group such as, for e~ample, methylsulfonyloxy or 4-methylphenyl~ulfonyloxy, whereas W may also be Cl ~alkylo~y and Cl 6alkylthioO

Th~ above ~-alkylation reaotion is con~niently conducted in an inert organic ~olv~nt ~uch as, or ~a~pl~, an aro~ati~ hydrocarbon, 0.g., b~nzen~, methylb~nz~ne, dimethylbenzen~ and the liX~; an al~anol, ~.g., methanol, ethanol, l-butanol and the like; a ketorLe, e.g., 2~propanone, 4-m~thyl-2-p~ntanone and the like; an ether, e.g., 1,4 dio~ane, l,l'-o~yhi~e~thane, tetrahydro~uran and the like: a polar aprotic solvent e.g., N,N-di.me~hylformamide (DMF), N,~-dim*thylacetamide (DMA), dimethyl aulfoxide ~DMS0), ~itrobenzen0, l-me~hyl-2-pyrrolidinone, and ~he like.
The additio~ o~ an appropriate ba~e ~uch a~, for a~ampl~, a~ alkali or an ear~h alkal;n0 metal carbonat~, hyd.rogen carbo~ate, hydroxide, amide or hydrld~, ~.g., ~odi~m carbonate, ~odiu~ hydrogen carbonate, pota~sium carbonate, ~odlum hydro~ide, calcium oarbonate, calc;um hydro~idQ~
~odium hydrid~, sodium ~mide and the like, or an or~anic base, Such as, :-! ` :o~ e~ampl~, a t~r~iary amine, e.g., E~ die~hylethanamine, ~ m~thyl-j :: : 25 ethyl)-2- pro2anamine, 4-~thylmorphol3.n~ and the li~e may be utili~e~l to pick up the acid which is liberated during the course of the reac~ion.
~: In some instancas the addition o a iodid~ ~alt, preferably an alkali m~tal iodide, iS appropriat~. Somewhat elevated te~peratures mhy enhance th~ rate of the reaCtion.
! 30 The compounds oP formul~ whQrein L is a radical oP ~ormula ~ l), (b-2), (b-3) or ~b-4), said radical L bein~ represented by the :1 ~ rad.cal L H-, and said compounds being represented by the ~ormula a~, can also be prepared by the reductive N-alkylation reaction of : ~ w;th an appropriate ke~one or ald~hyde of ~or~ula L =0 (IY), said ~ :
:: .

'I .
! ~

1 32~ 1 33 L =0 being an int~rmediate of formula L ~I2 wherein ~wo geminal hydrogen atoms are replaced by =0, and 1. = is a geminal bivalent radical comprising R -C1 6alkylidene, R -0 C1 6alkylidene, R R -~-Cl 6alkylidene and R -C(=0)-Z-C1 6alkylid2ne.

reductive N-alkylation L =0 + H-D _~ L ~-D

(YV) (II3 reaction ~I-a) ' Said reductiv~ ~-alXylation reaction may conveniently be carried out by ca~alytically hydrogenati~g a mixture of the reactan~s in a suitable : :
reaction-inert organic solvent according to art-known catalytic hydrogenating procedures. The reactisn mi~ture may ba stirred and/or heated in ord2r to eihance the reaction rate. Suitable solvents are, for axampla, water; lowar al~anols, eOg. methanol, ethanol, 2-propanol and ' the like, cyclic ethers, e.g. 1,4-dio~ane and the lik~; halo~enatedj hydrocarbons, ~.g. trichloromethane and the lik~ dimethylformamide7dim0thyl sulPo~id~ and the lik~; or a mixture of t~o os more o~ s~ch solvants. Th~ term "art-Xnown catalytic ~drog~nating procedures" means that the reastio~ is carrisd out und0r h~drogen atmospherc and in the pre~ence of a~ appropriate catalyst 3llch a~, or e~ample, palladium~
on-charcoal, platinum-on-charcoal and the lika. Ir, order to pre~ent the und~sir~d ~urther hydrogeration of cartain ~unctional group~ i~ the 1 25 reacta~ts and the ~aaction products it may b~ ad~antag~ous to add an appropria~ catalys~-poison to the reaction mix~re, ~.g., thiophene and the like.
: ~
~ The compounds of formula ~I) wherein L is a radical of formula ~b-2) i 30 wh~rein R4 i~ Arl, said R being represont~d by R and said compound~ by formula (I-b), may also he prepared by Q-alkylating an intermediate of ~ormula (V) with a reagent of formula (VI3 1 : ~
0-alkylation -a wl H0-Alk-D ~ R -~-Alk-D
~ VI) ~V~ (I-b) ',' ~ ' ':, .~ , .;' 1: , ~324133 Thfef compounds of formula SI-b) cfan also be prepared by 0-alkylating an intermediate of formula (VII) with a reagent of formula (VIII).

O~alkylatiff~fn R4~a_o_~ ~ Wl-Alk-D _ ~ (I-b) (VIII~ (VII) ::
Th~sf 0-alkylation ractions of (VI) with (V) and (VIII) with (VII) may be carried out by stirring the reactants, preferably at somewhat ff2~1evated temperaturfss in if n infert ff~frganic solvent ~u~rh as, for e~ fple, an aro~fatic hydrocarbon, e.g., hfenzene~ methylkfenzf2ne, dimethylbanzfene; a Xetone, fPf.g., 2~propanone, 0.!-me'ch~ 2-pan'canff~fne; an ethe~, e.g., l,4'L-diofxanffaf~ l,l'-frff%ybi3f~3fthanf~ff~ tetri~ydroL2uri~: and R polar i~protifc ~olvent, ef.ff3~ -dimfcfthylfcffrmi3mfide, ~,~-dimethylaf etamfidf2f; dimethyl .~ulfo:~idPf; :nitrofbfenzane; l-mffethyl-2-pyrrolidinfrffne; a~d the lil~ . The~
15 addition of a;~ appropriatfP base such as, for fs:~asr~ffple, an alkali metalcarbonatf~f or hydrogf2n carbonatfPf, sodiulr~ff hydridef or an organic base such a~, for ef~caf,rfple, N,~-diethylethanaminef or l~-~l-met~lel:hyl)-2-propa~-fomfine may be utiliz~fd ~ffro picf~k up the acld which i3 liberaff'f~f2ffd during the course sf t h~fa rffaac~ion.
', 20 Tha c~mpounds o~ formula (I3 wh~roi~ L i~ a radioal of form~la ~-4) wherein Z is ~;IR8 or O, 3aid Z b2i~g rofpresfsnted by Z a~d R is ~nino, Ar -amincf, Cl 6alk~l-i3mfino or ;~r -Cl 6if lkyl-am~nof, ~faid R being rf~ffprfssantf~ffd by 1~ 3nd said compounds by formula j 25 ~I-c-1), fran b~sf ~repared by reacti~g a~ isocyani3te of' ~cfrmula (X) with 1, rf_fagent of fsrmula (IX).

O
,1 ~ R7 ~ -Zl-Al~-D ~ R a_~m_C-Zl-AlX D

X) (IX3 (I-c-l) The eompounds of formula (I), wherein L is a radical o ~or~ula b 4) wh~rein Z is N~ and R is other than Ar or Cl 6alkyl ::
opt.ionally substituted with Ar , said R being represented by R7 ~, ( ~

-: ~

_9_ :
and said compounds being represented by formula ~I-c-2), can be prepared hy reacting an isocyanate of formula (~I~ wit~ a reagent o formula (XII).
O
R7-b ~ ~ O=C=N-Alk-D ~ R7-b C-~g-Alk-D

(XII) (XI) (I-c-2) The reaction of (X) with (IX), or (XIl) with (~I) is ganerally conducted ia a suitable ~action-inert solvent such as, for e~ample, an ather, a.g., tetrahydrofuran and ~he like. ~leva~sd temp~ratura~ may be suitable to enhance th~ rat~ o~ the reaction.

The compounds o~ formula ~I) wher0in L is a radical of formula (b-4) 15 wherein R7 i5 Ar or C 6alXyl optionally subs~itu~ed with Ar , .:
I and Z is ~IR~ or O, ~aid R being reprQsanted by R7 c and said i compounds by ~ormula (I-c-3), can ba pr~pared by r0acting a reagent of l formula (XIII) or a functional darivative thereof with an intermQdiate ¦ o~ formula lI~).
O O
R -C-OH ~ R C-c-~l-Alk ~ :
~ (XIII) ~I-c-3) ¦ 2S The reactio~ o~ (XIII) with (IX) may g~erally be conduct~d ¦~ ollowing art-known estari~ication- or amidation reaction procedures.
;~ For exampl0, the carboxylic acid may bc converted into a reactive derivativa, e.g., an anhydrid~ or a carboxylic acid halide, which ub~equently, is reac~ed with (IX); or by reacting ~X~II) and (IX) with ¦ 30 a suitabla r~3gent capable of forming amides or ~st~r3, e.g., dicyclo~
: ~ he~ylcarbo:diimida, 2-chloro-1-mathylpyridi~ium iodide ~nd the like. Said reac~ions are moat coaveniently conducted in a suitable solvent such as, ! ~or exampl~, an ether, e.g., tetrahydrofuran, a haloganated ~ydrocarbon, : ~ e.g., dichloromethan~, trichlorom~thane or a polar aprotic solvent. The addi~ion of a bas~ such as, N,~--diethyl~thanamine may be appropriat~.

~ ..
~.~ . '.' ~,, . ,, " ,. , ~ " . ., . ~ . " , " . , , ~ " j ~ ., , .. , , . . : ~

The compounds o formula (I~ wherein L i5 a radical of formula L -C2 6alXanediyl, said L being Ar -thio, Ar -sulfonyl, Ar , Cl 6alkylcarbonyl, Ar -Cl 6alXylcarbonyl, Ar -rarbonyl~ Cl 6alkylo3y~
carbonyl, Ar -Cl ~alkyloxycarbonyl or C3 6cycloalkyloxycarbonyl, and said compounds being represented by formula ~I-d~, ~ay be prepared by r~acting an appropriate alkenylene of formula (XIV) with a piperidine of formula SII).

L -C2 6alkenediYl-H ~ H-D ) L -C2 6alkanediYl-D
tXIV) (I~) ~I-d~

Th~ compounds of formula (I) wherein L is a radical o~E formula ~b-5), said compounds b~ing represent0d by ~Eormula (Y-e), may be preparsd by reacting a reag2nt of formula (XV) with a piperidine of formula (II)~

R9-0-CH2 ~ ~ H-D __ ) R -~-C~2-C~tO~ 2-D

, 20 ~XV) ~II) tI-~) ,I The reaction of (XIV) with (II), and ~V) with (II) may b~ conducted bystirri~g and, i~ desircd, heating the reacta~ts in a suitabl~ solv~nt auch as, ~or ~xa~pl~, an al~anono, 8.g. ~ 2-propano~e, 4-methyl-2-pe~tanon~, a~ ~th~r, e.g~, tetrahydro~Euran, 1,1'-o~ybisetha~, an i alcohol, e.g., metha~ol, ~tha~ol, l-blltanol, a polar aprotic solv~nt,e.g.~ -dimethyl~ormamide, N,~-dimethylaceta~ide and the like solvents.
1 ,~
Particular compounds wher~in L is methyl, said compounds being . 30 repr~ented by the ormula ~I-f), may also be prepared by reducing an ~:
~ intermadi~te of formula Cl 6alkyl-0-C~-O)-D (XVI) with 3U appropriate :~
I reductant such a3, for example, lithium tetrahydroaluminate in a ' suitable reaction-incrt or~anic so1vent, such as a lower alkanol.
.:~, . , ~' ~5 The compounds o~ formula (I~ ca~ al~o b~ ps~par~d by E-alkylating an .-j ' .
.~, ..

,:

1 32l~ 1 33 intermediate of formula (XVII) with an approprlate reagent of formula t XVI I I ) . , , R ~:

L-N~N ~ A--A2 ~ W-Alk-R
1~ l ... ............... ......... ............... ... ............................. ..... -~XVII) ~XVIII) Tha said ~-alkylation is conveniently earried out according to the proce~ur~s d~scrib~d her*;nabove for the pr~paration oX ~I~ tarting from (III) and tII).

The compounds of ~ormula (I) ~ay alternatively b~ pr~pared by the c~clode~ulfurization reaction of an appropriats thiour~a derivative of formula (XIX~, which ~ay in situ b~ ~Grmsd b~ cond~nsing a~
i~othioc~an2te o~ formula (X~) with a dia~ o ~ormula (XXI) Alk~R Alk L-~ll=C=S '~ 3 L 11~ 11 ~ i1 3 tX~) (XXI) (~IX) 6aid cy¢lodesulfurization reaction may b~ carried out by the reaction of t~IX) ~;th an appropriat~ alkyl halide, preferably iodomethane in an .
~, appropriat~ reac~ion-inert organi~ solvent, e.g., a lower alkanol such ¦ a~ methanol, ethanol, 2-propanol and the liXe. Otherwise, the cyclode- :
¦ ~ ~ul~uriza~io~ r~ac~ion may be carried o~t by the reaction o (XIX~ with i~ 30 an appropriats m~al O~ia~ or salt in an appropriato sol~on~ according ~:.
¦~ to art-kno~a pro~edures. ~or e~ample, the co~pounds of ~ormula (I) can ~
easily be prepared by the reactio~ of ~XIX) with an appropriate ~g~II3 ~.
or Pb(II~ oxide or salt, such as, for e~ample ~gO, ~gC12, ~g~OAc)2, PbO or Pb(OAc)~. In certain instances it may be appropriate to ~:1 35 su~plsmsn~ the raaction mixtur~ with a small amount of sulfur. ~en ~o :`:
l ; :.

'j. '.'":

1 32~ 1 33 methanediimines, especially ~ methanetetra71bis[cyclohe~an~nin~ may be used as cyclodesulfurizing agen~.

Or, the compounds of formula ~Ij ~ay be prepared by reacting a piperidine derivative of formula (XXII~ ~ith a benzimidazole derivative of formula (XXIII).
R Alk-R
L-~ 3 Q i ~ ~ A~ ~2 ~ (I) (XXII) 4,A

(~XIII) I~ (X~II) and (XXIlI) Q and Q are selac~sd 50 that during ~he reaction of ~XXII) with (~XIII) tha -~B - moiety i5 formed connacting the piparid;ne and b~zimidazole moi0ty.
For e~ample Q may ba a radical -N~R and Q a radical -W or lnversaly ~ may be a radical -~ a~d Q2 a radical -~HR .

~ R2 ~ ~ ~ A~ A2 ', ~ ,A
i ~XXII-a) A
' (XXIII-a~
,1 ' i ~ Alk ~ R2-N~ ~ ~ A ~ A2 ! (XXII-b~ A
1 . (~XIII-b~
'~1 ' 30 The r~actio~s o~ ~aXII-a~ with ~XXIII-a) and of (~XII-~) wi~h ~XXIII~
;' ar~ conveniently conduot*d in an iner~ organic ~olvent ~uch as, ~or ~xample, an aromatic hydrocarbon, e.g~, benzene, methylbenzene, dimathylbensene; a lo~er alkanol, e.g., methanol, ethanol, 1-~utanol; a ketone, e.~O, 2-propanone, 4-methyl-2-pentanona, a~ ether, e.g., 1,4~io~ane, 1,1'-oxybisethane, tetrahydrofuran; ~,~ dlme~hylformaml~e;

:

1 32~ 1 33 -13~
N,~-dlmethylacetamid~; nitrobenzene, dime~hyl sulfsgide; l~methyl-2-pyrrolidinones and th~ like. The additio~ of an appropriate base such as, for e~ample, an alkali metal carbonate or hydrogen carboaat~, sodium hydride or an organic base such as, for example, ~,N-diethylethanamine or N~ methylethyl~-2-propanamine may be utiliz2d to pick up the aoid which is liberated during the course of the reaction. In some circumstances the addition of a iodide salt, prefera~ly an alkali metal iodide, is appropriate. Some~hat elevated temperatures may er~ance the rat~ of the reaction.
Or, Q may be an oxo radical and Q a radiral -~HR .
R
L -N ~ O I (~XIII-h) . . .
i (XXlI-c) T~e reactio~ of ~XTI-o) with SXXII~-b) is convenie~tly carried out by stirring the reactants, pr~ferably at somewhat elevated temperatur~s, in ~ ~ suitable reaction-inert organic sol~ent with an appropriate reduc~ant.
i Pzeferably, th~ piperidon~ of formula (XXII-c) is ;rsk reacted with the ben~imidazol~amine of formula (XXIII-b3 to form an en~ina, whieh optionally may be isolat~d and ~rther purifi~d, and ~ub~egue~tly subjecting the said 0namine to a reduction r~action. Suitabl~ solve~ts , are, ~or e~ampla, ~ater, low~r alkanol~, e.g., methanol, ethanol, 1 2-propanol: cyclic ~ther~, e.g., 1,4-laioxa~: halog~nated hydsocarbons, i~ e.g., ~richlorometha~ -dimethylvrm~nide, ~ dimsthylac0tamids:
`1, 25 dimeth~l sul~o~id~ a~d th~ like; or a mi~ture o~ su~h solvents.~ppropriate reducta~ts are ~or example, metal or oomple~ metal hydrides, e.g. ~odlum borohydride, lithium aluminiumhydride: or hydrogen, the l~tter being pref~ably used in thc presence of a suitiable catalyst suc~
as, for ~ZZxample, palladium-on-charcoal, platinum-on-charcoal and the li~e. In order to pre~nt the ~nd~sired furth~r hydrogenation of certain ~unctional group~ in the r~actan~s and the r~action products it may be advantageous to add an appropriate catalyst-poison to the reaction , mixture, eOg. ~ thiophene and the lik~.
!
':'Z
¦ 35 Tho compound3 of formula (I) can also be converted in~o each other ,, .

i , ' ' ' ~ ` '; ' " ! ; . , ' ,' / . ' : i , ~; i, . .. . ! ' ~: , .' ' ' . , , ,, ', . ,: ,.,,, , ' '. , , ' .; ' , ', ;''," ' ' '' ' , ., . ' " . " ' ' ' ; " ' ' "

1 32~ 1 33 following art-known procedures of functional group transformation~ Some e~amples of 5uch proc~dures will be ci~ed herei~aft2r.
The hydrogen a~om o~ the amino ~unction(s) of compound~ of ~ormula (I) may be substituted following art-known procedures such as~ for ezamplc, ~-alkylation, N-acylation, r~ductive ~-alkylation and the like procedures. For example alkylcarbonyl, arylcarbonyl and the like groups may be introduced by reacting the starting amine with an appropriate carboxylic acid or a derivative thereoE such as, for example, an acid halide, acid ~hydride and the like.

In all o~ the foregoing and in ~he following preparations, the reaction products may b~ isolated from the reac~ion mi~tura and, l de~ired, further purifie~l according to methodolsgi~s generally Xnown in the art.
The compounds Q~ formula ~I) have bas;c properties and, consequently, they May b0 converted to their t~erapeutically active ! non-toxic acid addition salt orms by traatment with appropriate acid~,su~h as, 40r axa~ple, inor~anic acid~, such as hydrohaliG acid, e.g,, ~O hydrochloric, hydrobromic ~nd the lik~, and aul~uric acid, nitria acid, pho~phoric acid and the like; or orgallic acids, such as, ~ot e~ample~
acotlc, propanoic, hydro~yac~tic, 2-hydro~ypropanoic, 2-oxopropanoic, ¦ ethanedioic, prop3nedioic, butanedioic, (Z)-2-but~nedîuic, (E)-2-buten~-dioic, 2-hydro~ybutanedioic, 2,3-dihydro~ybutanedioic, 2-hydro~y-1,2,3-1 25 propan~tricarbo~ylic, ~thanesulfo~i~, etha~es~l~onic, b~nzene~ul~onic, ! ~-~e~hylben3enesulfonic, cyclohexanesulfamic, 2-hydro~yb~nzoic, i 4-amino 2-hydrox~benzoic and thP like acids. Conversely the salt ~orm I can be convert~d by treatment with alkali into the fr~e base form..
~'~ 3Q So~ o tho i~t~rmediates and starting materials in the f~regoi~g pr~parations are hlown compounds whils others ar~ no~el. Th~y may b~
1 pr~pared according to art-known methodologies of preparing sa d known or 1, similarly known compounds. Soma procedures ~or preparing such intormediates will be d~scribad hereinafter in mor~ detail.
', 35 .~ :

;, .
.. . .

The i~term~diates of formula (II) can convenie~tly be prepared following art-known proc~dures as described in, ~or ~ampl~, U.S. Patent ~os. 4,219,559, 4,556,660 and 4,588,722~

For exampl~, by cyclodesulfurization of an i~termediate of formula (XXIV) following the sam~ procedures as described hereinabove for the preparation o~ (I) starting from (XIX) a~d, subsequently eliminating the protective group P in the thus obtained intermediate of formula SXXV).
Alk-R AIk-R

P-B~ S ~A i I ~ I A a (X~IV) (~V) In (XXIV) a~ (XXV) P represen~s a protec~iv~ group which is readily removeabl~ by hydroge~ation or hydrolysatio~, ~uch as, phanylmethyl, Cl ,~alXylo~ycarboryl, arylCl 4alkylalkylo~ycarbonyl and th~ llke ,' group3.
2~
~ ~hc in~ermea~at~s of ormula (II) ca~ also ba prcpared by reacting a ] piperidin~ derivative of formula (XXVI~ ~ith a borlzimidazole derivatlve of ~ormula ~XXIII), following tha ~ame procedures as described hexeinabove or the pxeparation of (I~ starti~g from (~XII) aad tXXIII) 1 25 and, subsequently eliminating the protective group P in th~ thus ob~ained intermediate of or~ula (X~V).
.~ .
, p_~ ~ Q1 ~ (XXIII) __ _ ~ [XXV) .
l 30 ~XXVI) Intermediat~ of ormulàe (V), ~VII), ~lX) a~d ~XI) can convenientl~ be prepared ~ollswing art-known procedures as describe~ in, ~or example, U.S. Pat2~t No. 4~556,560 by ~alkylating an i~termediate o~ ~ormula (II~ wi~h an appropriate reagent ~ollowing a similar ~-alkylation ;~ .
. -, .

~7 :
, '' ,'', 1 32~ 1 33 procedure as described her~inabove for the preparation of 5I) starting from (II) and (III).

From formula SI) it is evident that the compounds of this in~ention may have several asymmetric carbon atoms in their structure. ~ach of these chiral centers may be present in a R- and a S-con~iguration, this R- and S-notation being in ~orrespondence with the rules described by R.S. Cahn, C. Ingold and V. Prelog in Angew. Chem~, Int. Ed. Engl., 5, ' 385, 511 (1966).
Further, the compounds of this invention wherein L is C~ 6alkenyl optionally substituted with Ar may be present as E and Z-forms, this ~- and Z-~otation being in corre~pondence with ~he rul~s also d~scrib~d in J~ Org. Chem~, ~5, 2849-2867 ~1979)a Pure stereochemically isomeric forms of the compounds of formula (I3 '! 15 may b~ obtained by the application o~ art-kno~ p~ocedur~sO
~ia~t2reoisomers may be separat~d by physical separa~ion method~ such as selective crystallization and chromatographie techniqu~s, e.g., courter ¦ current distribution, and enantiomers may be separat~d ~rom each other by the s~lecti~e crystallization of thair diaster~omeric salts with optically acti~ acids.
Pure st~reochemically isomeric ~orms may also be d~r~ved from the corresponding pura stersochemically i~omeric forms of ~he appropriate ~tarti~g materials, provided that th~ reaction occurs s~eroospecifically.
~ evident that the cis and trans diastereomeric racematcs may be i ~5 urther resolved into th~ir optical isom~rs~ cis~), cist-), trans~);~ ~ and trans(-) ~y the application of methodologi~s k~ow~ to ~hose s~illed ~; ~in th~3 art,.
`~ Stereochemically isomeric forms of thc compounds of formula tI) are naturally intended to be embraced within the scop~ of ~he invention.
The compounds of formula (I), the pharmaceutically accept~ble acid-addi.tion salts and possible stereochemically isomeric forms thereof possess useful pharmacological properties. More particularly, they are active as anti-histami~ics which ac~ivity is clearly evide~ced by e.g.
t~e results obtai~ed i~ the "Protection of ~ats from Compou~d j ~ ' ' '' ~' ., . ~ , . ~ .

1 3211 ~ 33 48~80-i~du~ed lethality"-test, the 'Histamin~ antagonism in Guinea-Pig"-test and the "Ascaris All~rgy t~st in Dogs"-test describsd in Arch. IntO
Pharmacodyn. Ther. 251, 39-S1 (1981~o Apart from their anti-histaminic properties some of the subject compou~ds also show serotonin-antagonism.
Furthermore the compounds of formula (I), the pharmaceutically acceptable acid-addition salts and stereochemically isomeric forms thereof are particularly attractive due to their favourable pharmaco-kinetical profile. In particularly, some eompounds show a rapid onset so that their aDti-histaminic ~ffects are almost irstantaneously prasent.
I 10 In vi~w of th0ir anti-histaminic properties, the compounds of ¦ formula ~ nd their acid-addition salts arQ very useful in the , tr~atment of allergic disease such as, for e~mple, allerqic rhinitis, ,, allergic conjunc~ivities, chron;c urticaria, allergic a~tma and the like.
In ~ie~ of their useful pharmaeological proper~i~s the subj~ct 15 ~ompounds may b~ formulate~ i~to various pharmaceutical form3 for administratio~ purposes. To prepare the pharmaceutical compositions of this i~v~ntion, an effoctive ~nount o~ the particular compoun~, in base or acid additio~ salt form, a~ th~ actiYe ingredi~nt is combined in i~timate admi~ture with a pharmaceuti~ally aeceptable carrier, which 20 earri~r may take a wid~ Yari~ty o forms deps~di~g on th~ ~orm of praparatio~ desired ~or admi~is~ration. Th~se pharmae~u~ical compositions ar~ de~lrably in unitary do3ag~ form suitabls, pr~ferably, ~or admini~tratio~ orally, r~ctally, ~ercuta~eou~ly, or by pare~t~ral inj~etio~ For ~xample, in prepari~g th~ compositio~ oral dosag~
25 for~, a~y o~ th~ u~ual pharmaeeutieal media may b~ employed, such ~3, for example, watQr, glycol~, oils, alcohols and the liXe in t~e case of oral liquid preparations such as suspensions, syrups, el~xiss and ~, solutio~s: ~r solid carriers such as sta~che~, sugars, kaolin, ~r lubricant~, binders, di~i~tegrati~g agents and ~he like in the case of 30 powdars, pills, cap~uleis and tablets. Beaause of th0ir ease in administration, tablets and aapsule~ represent the mo~t adv~ntage~us oral dosage unit orm, in which case solid pharmaceutical carriers are Z obviously employed. For parenteral compo~itions, the carrier will usually comprise sterile water, at least in lasge part, though other inqredients, for e~nple, to aid ~olubility, may be included. Injectable solutio~3, ~or e~ample, may b~ prepared in which the carri~r comprises `3 ~`
.

.- ~

1 .

~ 32l~ ~ 33 saline solution, glucos~ solution or a mixture of saline and ylucose solution. Injectable suspensions may also b~ prepared in which ca~e appropriate liquid carriers, suspendinq agents and the li~e may be employed. In the compositions suitable ~or percutan~ous administration, th~ carrier optionally comprises a penetration enhancing agent and/or a suitable ~etting agent, optionally combined with suitabl~ ad~itives of any nature in minor proportions, which additives do not introduce a significant deletorious effect on the skin. Said additives may facilitate the a~ministration to the skin and~or may be help~ul or lQ preparing the desired compositions. These compositions may be a~ninist0red in various ways, e.g., as a transdermal patch, as a ~pot-on, as an ointm0nt. Acid addition salts of (I~ due to their , i~creas2d wat~r sol~bili~y over the correspo~ding ba~e for~, are i obviously more suitable in the prepara~ion of aqueous compositions.
~, 15 It is e~pecially advantageous to formulate the aforemerltionsd pharmaceutical cornpositions in dosage unit ~orm ~or ease of administrati3n and unifor~ity of dosage. Dosage unit: form as used in the I, specifieat~on and claims herein ro~ers to physically discret~ units 1 s~itable as unitary do~ages, eaeh unit co~taining a pred~terminsd quantity of active ingredi~nt calc~lated ~o produce tha d~sired , therapeutic ef~ect i~ a~sociation with the required pharmac~utical .' carrier~ E~amples of such dosag~ unit for~ are table~s ~ncluding , scored or coate~ kablets), cap~ule~, 'pill$, po~rder paeXQts, w~fers,:j injectable solutions or suspensions, teaspoo~ful~, tabl~poonfuls and thQ li~e, and segregated multiples th~reof.
Tho present invQntiOn iS also related with a method of treating l allerglc dis~ases i~ warm-blooded animals sufferi~g from said allergic :, dise~ses by ad~inisteri~g ~n ef~ectlve a~ti-allergic amount o~ a ~I compouna of formula ~I) or a pharmac~utically accep~able acid addition salt there~
~' Those of ~kill i~ treating allergic ~isqases in warm-blooded ~nimals ~'~ could easily do~ermin~ the effective a~ount from the test results prese~ted hereinafter. In general it is contemplated that an effective amount wo~ld be from 0.001 mq/kg to 100 mg/kg body weight, and more preferably ~rom 0.01 mg/kg t~ 1 mg/kg body we;~ht. :
'~, ' ' J , -:
.~

1 32~ 1 33 Th~ followinq e~amples are intented to illustrate and not to limit the scope of th0 present invention in all its aspects. U~12ss other~rise stated all parts therein are by weightO

EXPERIMæ~TAL PART
A. Prepa ~tion of Intermediates Example 1 a) A mixture of 12.9 parts of 4-methyl-2-furancarboxaldehyde, ~.1 parts of hydro~ylamine hydrochloride, 11.9 parts of pyridine and 160 parts o 10 methanol was stirred overnight at room temperature. Th~ raaction mi~tur~
was evaporated an~ the residu0 was ta~en up in wa~er. The w~ole was acidified with concentrated hydrochlorlc acid and thc product ~as e~tracted wi~h l,l'-oxybisethane. The ~tract was washed with water, dried, filtered a~d evaporated, yielding 14 p rts (9~.6~) of 4-mathyl-15 2-urancarbo~aldehyde,o~ime as a residue (int. 13.
b) A mi~ture o~ 1~ parts o~ 4-methyl-2-furancarbo~aldeh~de,o~im~, 400 parts of methanol and 40 parts of 2-propanol, saturat0d with hydrogen I chloride ~as hydrogenated at nor~al pressure and at roo~ temperature J with 4 part~ o palladi~m-on-charcoal catalyst 10~O After the calculated 20 a~ount o~ hydrogen was taken up, the ca~alyst ~a~ Ziltered off and the ~ filtrate wa~ ~vaporated at 30~C. Th~ r~sidue ~as taken up in water a~d¦ saturated with potai3sium oarbonat~. Th~? product wa~ e~tracted ~i~h ;' l,l'-oxybisethana. The cS~trac~ was dried, fil~ered and eYaporated. Th~
residuc was puriied by column chromatography o~er sili~a gel using a 25 m~tur~ of trichlorom~tha~e and m~thanol, sa~uratad with ammonia, (95 5 by volumsei) as elue~t. The pure rac~io~s were collect~d a~d the eluen~
was evaporated, yielding 8 parts (64.2~) of 4-m~i?thyl-2-Eura~methanamine i as a ri?sidu~s (int. 2).
`ll c~ A mi~ture oP 10.4 parts of 2-chloro~3-nitropyridine, 8 parts of 30 4-met~yI-2-~uran~et~anamine, 7.6 parts o~ sodium hydrogen carbonate and 120 parts O r e~hanol wa~ s~irred ovQrnight at reflu~ temperature. The reaction mi~ture was evaporated a~d the residue was taken up i~ water.
, The product was extracted with l,l'-oxybisethane. The extract was dried, ~iltered and evapora~ed. The residue was purifisad by colum~ chromato-35 graphy over silica gel using t~ichloromethane as ~luent. The pure '`I ~ .

~,i . .
.`~, .

13?4 1 33 fractions were collected and the eluent was evaporate~, yielding 1~.9 parts (91.2~) of N-[(4-methyl-2-furanyl~methyl]-3-nitro-2 -pyrid inamine as a residue (int. 3).
d) A mixture of 14.9 parts of N-[(4-methyl-2 fura~yl)methyl]-3-nitro-2-pyridinamine, 2 parts of a solution of thiophene in methanol 4~ and 320parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-o-n-charcoal catalyst 5~. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 14.2 par~s (100~) of N -fL(4-methyl-2-furanyl)methylJ-2,3-pyridinediamine as a residue (int. 4).
In a similar manner there w~rs also prepared:
~(5-methyl-2-uranyl)methyl]-1,2-b~ze~ediamine as a r~sidue (int. 5), ~2--[~5-mathyl-2-furaayl)methyl]-2,3-pyridinediamine as a residue tint. 6);
N -r~(Z-m~thyl 3-fura~yl)mcthyl]-2,3-pyridinediamine as a residu~ (int. 7);
-t(5-ethyl-2-furanyl)methyl]-2,3 pyriainediami~e as a residue (int. 8);
N~-~t5-mathyl-Z-~uranyl~methyl3-3,4-pyridi~ediamine as a residue (int. 9)s N2-~(3-methyl-2-furanyl)methyl]-~,3-pyridinediamine as a residu~ (int.10);
N t(5-methyl-2-fur~yl)ma~hyl]-3,4-pyr3Ldinedi3mi~0 as a residue (int.ll);
, 20 and ~ -t~5~ methylethyl)-2-furanyl]m~\~hyl]-2,3-pyridinediamine as a ¦ ~e~id~e (in~O 12).
Exampl~ 2 a) A mi~turs o~ 68.5 parts of ~thyl 4-~Lsoth~Locyanato-1-pip0ridinecarboxy-late, ~a.o parts of ~ -~t5-ethyl-2-furanyl)met~yl]-2,3-pyridinediamine ~ 25 an~ 450 parts of t~trahydrofura~ wa s1;irred ov~rnight at re lu~
¦ temperature. A~ter e~aporatio~, tha residue ~as purified by column chromatography over ~ilica gel using a mi~ture of trichloromethano and mathanol (97:3 by volume) as eluent. The purc fractions were collected and th~ eluent was evaporated. The residne was stirred in l,l'-oxybis-athane. Th~ product was ~iltered off and driea, yiel~ing 50 parts ~, ~44.4~) o~ ethyl 4-t[[~2-~[~5-ethyl-2-uranyl)~ethyl]aminoJ-3-pyridinyl~-amino]thio%omethyl]amino]-1-piperidinecarbo~ylate (int. 13).
b~ A mi~ture of 50 parts of ethyl 4-~[~t2-~(5-ethyl-2-furanyl)methyl]-am~ro]-3-pyridinyl]amino]thio~omethyl]ami~o]-1-piperidinecarbo~ylat~, 32.4 par~s of mercury~II) o~ide and 480 parts of etha~ol was stirred for ", .

:1 ~

1 32~ 1 33 1 hour at reflux temperature. The reaction mixtura was filtered over diatomaceous earth and the filtrate was evaporated~ The residue was stirred in 1,1'-oxybissthan0. The crystalli~ed product was filtered off and dried, yielding 38 parts (83.1~) of ethyl 4-[~3-~(5-ethyl-2-furanyl)methyl]-3H-imidazo~4,5-b]pyridin-2-yl3amino]-1-piperidinecar-boxylate; mp. 111.1C (int. 14). In a similar manner there were also prepared:
ethyl 4-~l-C(5-methyl-2-furanyl~methyl~-lH-benzimidazol-2-yl]amino]-l-piperidinecarbo~ylate hemihydrate; mp. 150.1C (int. 15);
~ ethyl 4-[~3-l~5 methyl-2-furanyl)methyl]-3~-imidazo[4,5-b]pyridin-2-yl~amino]-1-piperidinecarboxylate as a residue ~int. 16~;
~thyl 4-t[3-~2-m~thyl-3-furanyl3m~thyl]-3H-imidazo~4,5-b]pyridin-2-yl]amino3-1-piperidinec~bo~ylat~, mp~ 153.7C (;nt. 17);
ethyl 4-[tl-~(5-m~thyl-2-furanyl)methyl]-lH-imida~ot4,5-c~pyridin-2-yl]amino]-1-piperidinecarboxylate; mp. 155.2C (intO :L8);
ethyl 4-t[3-[(3-methyl-2-furanyl3methyl]-3H-imidazo~4,5-b3pyridin-2-yl]aminoJ-l-piperidinacarbo~ylate as a residue ~int. 19);
ethyl 4-t~3-t(5-methyl-2-furanyl)methyl~-3H-imida~o~4~5-c]pyridin-2-yl~amino~ pipariain~carboxylate ~int. 20);
20 ~thyl 4-t[3-[t5-(1-m~thyl~thyl)-2-fl~ra~yl]methyl]-3H~imidazo~4,5-~3-pyridin-2-yl3amino]1-piperidinecarbs~ylat~ as a re3idue ~int. 21); and e~hyl ~-~t3-[(4-methyl-2-fura~yl)methyl]-3~-imîda~o L4, 5-b~pyri~in-2-yl]~mino]-l-piperidinecarbo~ylat0 as a residue ~int. 22).
~x~mple 3 To a stirr~d mixture of 4.6 parts o a sodium hydrid~ dispcr3ion 50~
and 450 par~s of N,~-dimethylformamide wer~ added portionwise 57.6 parts o~ ~thyl 4-~1~-benzimid~zol-2-ylamino~-1-piperidinecarboxylate under nitroge~ atmosphere. Upon complete addition, stirring was continued for 30 minutes at room temperature. 27.0 Par~s of 3-(chloromethyl)-2-methyl-, 30 furan w0r~ add~d dropwice while cooling. Upon completiou, stirring was ', ao~ti~usd ~or 1 hour. Wat~r was addea dropwise to the mi~tur~ and tha product was extracted with 4-methyl-2-pentanone. The e~tract was drie~, iltered and evaporated. The residue was st;rred in 1,1'-oxybis~than~. -The solid product was filtered of and purified by column chroma~ography 3S ovar si1ic~ g~l u~ing a mi~ture of ~richloromethane and methanol (95:5 ' by volslme) a~s eluent. Th~s pure fractions were colle ted and the eluens~
was evaporatied. Thes residue was stirred in l,1'-o~ybisethane. The produrt was filtered off and dried, yielding 37.5 parts (13.0~) of ethyl 4-[[1-[(2-m~thyl-3-furanyl)methyl]-lH-benzimidazol-2-yl]amino]-l~piperi-dinecarboxylates mp. 150.4C ~int. 23).
In a similar manner there was als~s prepared:ethyl 4-[[l-(4-thiazolylmethyl)-la-benzimidazol-2-ylsamino3-l-pip~sridine carboxylate, mp. 156.2C (int. 24) Example 4 A mi~ture of 20.5 parts of ethyl 4-~[1-[(5-methyl-2-furanyl)mcS~hyl3-lH-imidazot4,5-c]pyridin-2-yl]amino"-1-pip~ridinecarbcs~ylate~ 40 parts of po~assium hydrn~ide and 240 p~rts of 2-propianol was stirred overnight at reflsl~ temp~rature. Aft~r evapsoration, the r~sidue ~as tak~n ~p iS
wat~r and tha product was e~tracted ~ith dichloromethan~. The e~tract 15 was dried, ~iltered and evaporated. The residue was crystallized ~rom 2 propanone~ The product was filtered off and dried, yielding 15 parts (88~ of 1-t~5-methyl-2-~uranyl)methyl~-N-(4-piperidinyl)-lH-imidazo-t4,5-c]pyridi~-2-amin6,; mp. 185.6C (i~t. 25).
In a similar ma~ner thier0 wer~ also prepared:
1-~(5-mathyl-2-fura~13methyl]-~-~4-piperidinyl3-lH-be~zimidazol-2-a~ e a5 a re~idu~ (int. 26):
N-(4-pip~idinyl3~ thiazol~lmethyl~-lH-be~zimidazol-2-amine dlhydrobromid~.monohydrat0, mp. 223.5C (int. 27);
3-t(5-methyl-2-furanyl)methyl]-1~-(4-piperidinyl)-3~1-imidazo[4,5-b]py~idin-, 25 2-amins; mp. 120~C (int. 28);
,. 3-~t2-m0thYl 3-furanyl)methyl]-'1~-(4-piperidinyl)-3X-imidazot4,5-b]pyridin-J 2-amine: mp. 165C ~int. 29 3-~(5-ethyl-2-furanyl)methyl]-~-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine; mp. 106C (int. 30);
30 1-t(2-methyl~3-furasnyl)methylJ-~-(4-piperidinyl)-lH-benzimidazol-2-amine:
mp. 168C ~int. 31), `~
3~~3-methyl-2-furanyl)methyl] ~-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine; mp. 160C (int. 32);
' 3-~(5-m~thyl-2-ur~nyl)methyl',-'~-(4-piperidinyl~-3~-imidazot4,5-c]pyridin-2-a~ e hemihydrat~; mp. 146~C (int. 33), ,~ ,, ''-1 324 ~ 33 3-[[5-51-methylethyl)-2-furanyl3methyl3-~-(4-piperidinyl)-3H-imidazo-[4,5-b]-pyridin-2-amine dihydrochloride; mp. 235C tint. 34); and 3-[(4-methyl-2-furanyl3methyl]-~-(4-piperidinyl)-3H-imidazot4,5-b]pyridin-2-amine, mp. 143C (int. 35).

5 Example 5 a) A mixture of 2 parts of 2-chloroacetonitrile, 8 parts of 1-~(5-methyl-2-furanyl)methyl]-~-(4-piper dinyl)-lH-benzimidazol-2-amine, 3.1 parts of sodium carbonate and 90 parts of ~,~-dimethylformamide was stirred and heated overnight at 45C. The reaction mixture was poured into water 10 and the product was e~tracted with dichloromethana. The e~tract was dried, iltered and evaporated. The residue was crystall1zed from a mi~ture of acetonitrile and 2,2'-o~ybispropane, yi01~i~g 7.3 parts (80.4~) o~ 4-tt~-r(5-methyl-2-furanyl)methyl]-1~-benzimida~ol-2-yl]-amino~ piperidineacetonitrile; mp. 177.3C (int. 36)~
15 b) A mixture of 6 parts of 4-E~ (5-methyl-2-fu~anyl)methyl~
~enzimidazol-2-yl]amino]-1-piperidineace~oni~rile and 233 parts of methanol, saturat~d ~rith ammon a was hydrogenated at normal pressure and at room t0mperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was take~ up, the cat~lyst wa~ filtered 20 of~ a~d the filtrate was evaporated, y~elding 6 parts of ~-tl-(2-~nino-ethyl)-4-piperidinyl]-1-~5-methyl-2-furanyl)msthylJ~ b2nzimidazoï-2-amine as a re~idue (i~t. 37~.

8, Pre~aration of Final ~ompounds ~I Z5 88~crlçLL_ I A mixture of 3O32 parts of 1-(2-bromoethyl)-4-ethyl-1,4-dihQdro-SH-tetrazol-5-one, 4~65 parts vf l-t(5-methyl-2-furanyl)m~thyl]-~-(4-piperi-d;nyl)-1~-benzimidazol-2-amine, 1.6 parts of sodium carbonate and 45 ~ parts of N,N-dimethylacetamide was stirred overnight at 80C. The J 30 reaction mixture was poured into watar and the product was extracted , with 4-methyl-2-pentanone. The e~trac~ was dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent.
, The pu~e fractions were collected and the elue~t was evaporated. The i 3~ re~idue was converted into the ethanedioate salt in methanol. The salt .~ , .
,~

, ':
, ~

1 32~ 1 33 -2~-was filtered of~ and dried, yielding 5.2 parts t55~) of l-ethyl-l,~-dihydro-4-[2-t4-~ (5-rnethyl-2-furanyl)methylJ-lH-benzimidazol-2-yl]-amino]-1-piperidi~yl]ethyl]-5H-tetrazol-5-o~e ethanedioate~l:2~;
mp. 190.5C (compound 22).
ExamplP 7 A mixture of 3.9 parts of 2,3-dihydro-1,4-benzodioxin-2-m~thanol methanesulfonate(ester~, 7.4 parts of 3-t(5-methyl-2-furanyl)methyl]-~-(4-piperidinyl)-3H-imidazot4,5-b]pyridin-2-amlne, 5.3 parts of sodium carbonate a~d 90 parts of ~,N-dimethylacetamide was qtirred overnight at 80C. The mi~ture was poured into water and the product was extracted with 4-methyl-2-pe~anone. The e~tract was dried, filter~d and evaporated. ~he residus was purified by column chzomatography o~er silica gel using a mi~ture o trichloromethane a~d metha~ol ~96-4 by volume) as eluent. Tha pure fraction~ were coll~cted and the eluent was evaporated. '~he residue wa~ convert~d i~to the ethanedioat~ salt i~
methanol. The salt was filtered oPf and dried, yielding 2.2 parts (23~) of ~ (2~3-dihydro-1,4-b0nzodio~i~-2-yl)methyl]-4-pip~ridinyl]-3-~(5-methyl-2-uranyl)methyl~-3~I-imidazot4,5-b]pyridin-2-aTnine :~
ethanedioate~l:2); mp. 222.3C (oompound 14~. -E~ mpl~
I A mi~ture of 1.2 parts o~ 1-chloro-;!-etho~yethan~, 3.1 parts o~
¦ 3-[(2-methyl-3-furanyl)methyl]~ g~pi1?0ridinyl~-3~-imidazo~4,5-b]pyridin-' 2-amirl~, 1.6 part~ of 30dium carbonate and 45 part~ of ~,N-dimethyl-'~ ormamid~ wa~ stirrod ov0rnight at 70l:. Th~ rsaction mi~ture was pour~d i~to 50 parts o~ ~at~r. Petroleum ath~r wa~ added and a4ter stirri~g, I the cryst~llized product was filtered off, washed with water and p~troleum ethsr a~d stirred i~ 1,1'-oxybisetha~e. The product was I filtered off and dried at room temperature, yielding 1.6 parts ~38.1~
¦ o~ ~-El-[2-etho~ysthyl)-4-pip~ridi~yl]-3-r~2-methyl-3-uranyl)methyl] 3H-~ 30 imidazo-~4,5-b~pyridin_2_ami~e dihydrat~, mp. 8405C (compound 32).
`'1 ~9~ :-A mixture of 1.82 parts of 3-bromo-1-propene, 7.4 parts of 3-~5- -~
methyl-2-furanyl)methyl]-N-~4-piperidinyl~-3H-imidazo~4,5-b]pyridin-2-amine 0~hanedioate (2~ .2 parts of sodium hydrogen ~arbonate and 120 35 parts of ethanol was stirr~d overnight at re~lux temperature. The l `.
J ~
. 1 :
.
.~ .,.

1 32~ 1 33 2~-reaction mi~ture was filtered and the ~Eiltrate ~as evaporated. Th~
residue was ~aken up in ~7ater and the product was e~tracted with triehloromethane. The extract was dri~d, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure f ractions were collected and the eluent was evapora~ed. The residue was converted into the (E)-2-butenedioate salt in a mixtur~ of 2 propano~e and methanol. The salt was filtered off and dried, yielding 2 parts (23~ sf 3-[(5~methyl-2-furanyl)methyl]-~-[1-(2-propenyl)-~-10 piperidinyl~-3H-imidazo-~4,5-b]pyridin-2-amine (E)-2-butenedioate~1:2):
mp. 172.7C (compound 5).
E~ample 10 A mixture of 2 parts of pol~(oxymethylene3, 4.5 parts of 3-tt5-methyl-2-uranyl)methyl]~ -piperidinyl)-3H-imidazot~,S-b]pyridin-2-arnine, 1 lS part of a 801ution of thiophene in metha~ol 4~ and 120 parts of methanol was hydrogenated at normal pressure and at 50~C with 2 parts of platinum-on-eharcoal ~a~alyst 5~. After the ~al~ulated amount of hydroge~ was take~ up, the catalyst was filtered off over diatomac~ous earth and the rate was ~vaporated. The r~sidue was purified by column chromato-20 graphy ov~r silica gel using a mixture o~ trirhloromethane and methanol,saturated with a~mo~ia, (96:4 by volum~) as eluent. Th~ pur~ ~raction~
w0r~ collested and the ~lu~nt was evapora~d. Th~ residua was , crys~alliz~d from acetonitrile, yieldi~lg 0.7 par~s ~14~3~) o~ 3-~(S-;1 methyl-2-~ura~yl~mQthyl~ methyl-4 piperidi~yl)-3EI~imida~o[4,5-bJ-25 pyridi~-2-amine; mp. 131.0C (oompou~d 1~.
~x~mpl~ 11 .,, -~ A mixture of 5 parts o~ a s~lution o~ acetaldehyd2 in t~trahydro-i ~uran, 301 parts oP 3-~(S-m0thyl-2-furanyl)methyl]-~-(4-piperidinyl)-3~_.' imidazor4,5 b]pyridi~ 2-~mine, 4.5 parks of tetrahydrofuran, 1 part of a30 solution of thiophenQ in metha~ol 4~ and 200 pasts of methanol wa~ ~
hydrogena~d at normal pressure and at room temp~rature with 1 part o~
palladium-on-charcoal catalyst 10~. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was co~ert~d i~to the (E)-2-butenedioate 35 salt i~ ~thanol. Th~ salt was ~iltered off and dried, yi~lding 2.2 parts "~I ' :~ .

(38.5~) of ~ ethyl-4-piperidinyl)-3-[(5-methyl-2-furanyl)methyl]-3H-imidazo~4,5-b]-pyridin-2-amine (E)-2-butenedioate(1:2~: mp. 205.4C
(compound 4~.
Example 12 A mixture of 1.1 parts of 3-buten0-2-one, 4.7 parts of 3-[(5-methyl-2-furanyl)methyl]-N-(4-piperidinyl)-3H~imidazo[4,5-b]pyridin-2-amine and 120 part~ of ethanol was stirred Eor 3 hours at refux tPmperature. A~ter evaporation, the residue wa~ purified by column chromatography over silica gel using a mixture of triohloromethane and methanol (96:4 by lO volume) as eluent. Thç pure fractions ~ere collected and the eluent was evaporated~ The residu~ was converted i~to the ethanedioate salt in me~hanol. The sal~ was filtere~ of~ and dried overnight in v2cuo a~
lOO~C, yielding 1.8 parts ~21.3~) of 4-~4-~3~(5-methyl-2-furanyl)-methyl]-3H-imidazo[4,5-b]pyridin-2-yl]amino]-l-piperidinylj-2-butanone 15 ethanedioatell:2); mp. 164.1C. (compound 41), ~-E~ampla 13 A mixture o~ 4.5 part~ of 2-~pheno~nethyl)oziran~, 4.65 parts of 1-[(5-methyl--2-furanyl~methyl]-~-(4-piperidinyl)-1~-benzimidazol-2-amine and 120 part~ of methanol was stirred overnight at room temperatur2. Tha 20 precipitated product was filtered of~ and dried, yield;ng 3.1 parts (44.~) o 4-[[1-[(5-methyl-2-furanyl)methyl~ -ba~zimidazol-2-yl]-~mino]-a-(phenoxyme~hyl)-l-piperidineathanols mp. 164~8C (compound 2 ~; ) o ,X~m~ " ~
A mi~t~r~ o~ 0.1 parts of isocyanatomethane, 2.5 par~ of ~-~1-(2-aminoethyl)-4~piperidinyl]~ 5-methyl~2-furanyl)methyl~-7 -b~nzimidazol-2-amine and 135 parts of ~etrahydrofuran was stirred for 3 hours at room ~emperatureO The pre~;pitated produ~t was filtered o~f a~d dried, yialding ~.Z parts (41.1~) o ~-methyl-N'-t2-~4-t[1-~5-methyl-2-furanyl) 30 methyl]-lH-benzimidazol-2-yl3amino~-l-piperidinyliethyl]urea;
mp. 200.1C (compound 40j.
~xample 15 To a stirred mixture of 11.5 parts of ~-(1-methyl-4-piperidinyl)-lH-b2n~imidazol-2-amine and 1~4 parts of N,N-dimethylformamide were ~dded 5 :~ , J

parts of a sodium hydridç dispersion 50~. Aftar stirr;ng for 1 hour at room temperatura, a solution of 12.8 parts o~ 2-(chloromethyl)pyrazlne in N,N-dimethylformamide was added dropwise to the thus obtained mixture.
Upon complete addition, stirring was continued for 2 hours at 50C. The reaction mixture ~as pour~d into water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated.
The residue was purified by column chromatography over silica gel using a mi~ture o~ trichloromethane and methanol, saturated with ammonia, (96:4 by volume) a eluent. The pure ~ractions were colle~ted and the 10 eluent was ev~porated~ The residue was crys~allized from acetonitrile.
The product ~as filtered o~ and driedr yielding 1.5 par~s ~9.3~ of N~ methyl-~ piperidinyl)-1-(2-pyrazi~ylmethyl3-lH-benzimidazol-2-amin~:
mp. 169.3C (compound 69).

15 All other compounds li~ted in table 1 were ob~ain0d by analogous method~
of preparatio~ as described i~ examples 6-15, the aetual method o~
pr~paration boing indicated in column 2 ~"E~. no.").

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~.' .' .' C) Pharmacoloqical E~amples The useful anti-hista~inic properties of the compound~ of formula (I) which can be used as the active ingredient in the iEormlllations according to the present invention can be demonstrated by the following test procedure.
Example 16 Protectio~ of rats from compound 48/80-induced lethality.
Compound 48i80, a mi~ture oiE oligomers obtained by condensation of 4-methoxy-~-methylb~nzeneethanamine and iEormaldehyde has been describ0d as a potent histamine releasing agent ~Int. Arch. Allergy, 13, 336 i tl958~. The protection from compound 4B/80-induced lethal circulatory collapse ~pp~ars to b8 a simpl~ wa~ of evaluating ~uantitatively ~h~
antihistaminic act;vity oiE ~e~t compou~ds. Male rats o an ir~red ~istar , s'crain, weighing 240-260 g wer~ us~d in the ~perim~nt. AiEter o~ernight ~, 15 starva~ion ~he rats wsr~ trans Eerred to cGndition~d laboratories ( temp .
- 21 ~ 1C, relativ~ humidity = 65 ~ S~).
The rats w~re treated subcutan~ously or orally with a t~st compou~d or ~ with the solvent ~NaCl solution,. 0.5~)0 On0 hour after traatment thcre1 was injected intravenously co~pound 48~80, iEr~3shly dissolv~d i~ wat~r, at a do~e oiE 0.5 mgtkg (0.2 ml/lD0 9 oiE body weight). In control e~cper;me~ts, wherei~ 250 solv~nt-tr~3atl3d animals were in~cted with the , ~anda~d dose of compound 48/80, not more than 2.8~ of the animals i survived aft~r 4 hours. Survival aiEter 4 hour~ i3 thereiEo~e consid0red ~I to be a sae esite~ion of a protectiv~ e~iEe~t oiE drug administration.
25 Th~ ED50-values of the oompounds o~ formula (I) ~r~ listed in ~able 2 Said EDsO-values are the valu~s in mg/kg ~ody w~igh~ at which the l te~t~d compounds protect 50~ o the tested ani~als against compound ¦ 48/80-induced lsthali~y.

:
~1 , ,' .

,'1 i, :
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Table 2 _ compound 48/80 5 No. 12thality test in rats-ED50 in mg/kg body wei.ight 1 0.005 4 0 . OO~i5 0.005 ~ 0.04 .
7 0~02 :
8 0.~4 9 0.02 :
0 . 04 11 0.0~ ~ '',;
13 ~.OJ~
0.04 .l 18 0.01 22 0.04 :~ . 26 0.~4 29 0.04 36 ~.04 ~ i7 0 . 02 f ~ 25 3a 0.02 -~, ~i9 0 . 04 i ~0 0.02 ~, gl O . 01 'ii~ 42 0.04 '7i 30 46 0.0~
~j~ 53 ~.04 56 0.04 62 0.1~05 ;;
: 63 0.04 64 0.04 -I ~ . .
:1 ~ ' .~ .
! :
'i D) Composition Examples The following formulations exemplify t~pioal pharmaceutical compositions in dosage unit form suitable for systemic administration to animal and human subje~ts in acco~danca with the instant invention, "ActiYe ingredient" (A.I.) as used throughout these examples ~ ralates to a compound of formula (I) or a pharmaceutically acceptable ,' acid addition salt thereof.

Example 17 : ORAL_DROPS
500 g of the A.I. was dissolved in O.5 1 of 2-hydro~ypropanoic acid and 1.5 l o~ the polyethylen~ glycol at 50~80C. After cooling to 30~40C there were added 3S l of polyethylene gly~ol and th~ mixture ~as stirred well. Then there was added a solution oE 1750 g of sodium , saccharin in 2.5 1 of purified water a~d while stirring there were added ', 15 2.5 l of cocoa flavor and polyethylene glycol q.sO ~o a volume of 50 l, I pro~iding an oral drop solution comprising 10 mg of the A.I. per ml. The ', resulting solution was filled into suitable oontainers.
" ' ~,.
Example 18 : ORAL SOLUTIO~
9 g of methyl 4-hydro~ybenzoate and 1 g of propyl 4-hydro~y-benzoate were di~solYed in 4 l o~ boiling purified w~ter. In 3 l of this solution w~r~ dis~olved fis~t 10 g of 2,3-dihydro~ybutanedioic acid and thQrea~ter 20 g of the A.I. Th~ latte~r ~olutio~ was combined ~ith ~hP
remain;~g p~rt of the ~orm~r solutioII a~d 12 l 1,2,3-p~opane--triol and 3 ~i 25 l o~ sorbi~ol 70~ solution ~ere added t~reto. ~0 q of sodium saccharin were di~solv~d in 0.5 l o~ water and 2 ml of raspberry and 2 ml o~
gooseberry es~enoe were added. Th~ latter solution was combin~d w1th the formsr, ~at~r ~as added q.s. ~o a volume of 20 1 providing an oral solu~ion comprising 20 mg o~ the active inqradient per teaspoonful (5 ml~. Tha resulting solution was fill~d in suitable containers.
.~ .
Example 19 : CAPS~LES
20 g of the A.I., 6 g sodium lauryl sulfate, 5~ g starch, 56 g lactose, O.B g colloidal silicon dio~ide, and 1.2 g magnesium stearate ~ere vigorously stirred together. The resulting mi~tur~ was ~ubsequently . :"
::' ':, ., : .
~' '1 . .

1 32~ ~ 33 filled into 1000 suitable hardened gelating capsules, comprising each 20 mg of the active i~yredient.

~ample 20 : FILM-C0ATED TABLETS
Preparation of tablzt core A mixture of 100 g of the A~I., 570 g lactose and 200 g starch was mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone tRollidon-K 90~) in about 200 ml of water. Tha wet powder mi~ture was sieved, dried and sieved again. Then there was added 100 g microcrystalline cellulose ~Avicel~ and 15 g hydrogenated v~getable oil (5tero~e~ ~). The whole was mi~ed well and ~ompr~ssed into tablets, gi~ing 10.000 tablets, aach containi~g 10 ~g of th0 acti~e i~gredient. ~ -Coatina lS To a solution o~ 10 g m2thyl cellulose (Methocel 60 H~) in 75 ml o~ denaturaked ethanol there was added a solution o~ 5 g of ethyl cellulose ~thocel 22 cps ~) in 150 ml of dichlsromethane, Then there wer~ added 75 ml of dichlorometha~e and 2.5 ml 1,2,3-propan~-triol. 10 g I o~ poly~thylsne glycol ~as molten a~d dissolved in 75 ml o~
i 20 dichloromothan~. Ths latter solution ~las added to th~ ~ormer and then there ~re added 2.5 g o~ magnesium octadecanoat~, 5 g o~
polyvinylpyrrolidone and 30 ml of concentrated colour suspension (Opaspray K-1-21090~ and the whola wa~; homogenated.
~ho tablet cores were coated with the thus obtain~d mi~ture in a coating apparatus.

ExamplQ 21 : I~JECTABLE SOLUTION
1.8 g meth~l 4-hydro~ybenzoate and 0.2 g propyl 4-hydroxyb~n~oate ¦ ~ wer~ dissolved in about 0.5 1 of boiling water for inj~ction.
1 30 Aftercooli~g to about 50C thero we~e add~d while stirring 4 g lactici~ acid~ 0.05 g propylen~ glycol and 4 g of tha AoI~
$h* solution was cooled to room temperature and supplemented with water l ~ ~or inje~tion g.s. ad I I volume, giYing a solution of 4 mg ~.I. per ml.
;1 ~ Th~ solution was sterilized by ~iltration (U.S.P. XVII p. 811) and ~ 35 fill~d in st~rile co~tai~ers.
'1 .

,j '':
.~ ~

', ~

~ 324 1 33 ~xample 22 : SUPPOSITORIES
3 g A. I . was dissolved in a solution of 3 g 2, 3-dihydrogybutanedioi acid in 25 ml polyethylene glycol 400. 12 g 5urfactant ~SPAN~3 and triglycerides (Wit~psol 555 ~) q.s. ad 300 g were molten to~ether. The latter mixture was mixed well with the former solution. The thus obtained mixture was poured into moulds at a temperature of 37~38DC to form 100 suppositories each containing 30 mg of the acti~2 ingredient.

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Claims (20)

1. A chemical compound having the formula (I), a pharmaceutically acceptable acid-addition salt or a stereochemically isomeric form thereof, wherein:

A1=A2-A3=A4 is a bivalent radical having the formula -CH=CH-CH=CH- (a-1), -N=CH-CH=CH- (a-2), -CH=N-CH=CH- (a-3), -CH=CH-N=CH- (a-4), or -CH=CH-CH=N- (a-5);
wherein one or two hydrogen atoms in said radicals (a-1)-(a-5) may, independently from each other, be replaced by halo, C1-6alkyl, C1-6alkyloxy, trifluoromethyl or hydroxy;
R is hydrogen or C1-6alkyl;
R1 is furaryl substituted with C1-6alkyl, pyrazinyl, thiazolyl, or imidazolyl optionally substituted with C1-6alkyl;
R2 is hydrogen, C1-6alkyl, C3-6cycloalkyl, Ar3-C1-6alkyl or (C1-6alkyl)-CO;
L is C3-6alkenyl optionally substituted with Ar3, or L is a radical of formula -Alk-R3 (b-1), -Alk-O-R4 (b-2), -Alk-N-(R5)-R6 (b-3), -Alk-Z-C(=O)-R7 (b-4), or -CH2-CH(OH)-CH2-O-R9 (b-5);
R3 is hydrogen, Ar1-thio, Ar3-sulfonyl, 4,5-dihydro-5-oxo-1H-tetrazol-1-yl being optionally substituted in its 4-position with Ar3 or C1-6alkyl, 2,3-dihydro-1,4-benzodioxin-2-yl, 2,3-dihydro-1,4-benzo-dioxin-6-yl, 4-morpholinyl, 1-piperidinyl of 1-pyrrolidinyl, or when R1 is furanyl substituted with C1-6alkyl and A1=A2-A3=A4 is a bivalent radical of formula (a-1) or (a-2), R3 may also be Ar1,

2,3-dihydro-2-oxo-1H-benzimidazol-1-yl or 1-(C1-6alkyl)pyrrolyl;
R4 is C1-6alkyl or Ar1;
R5 is C1-6alkyl optionally substituted with Ar2;
R6 is Ar2 or C1-6alkyl optionally substituted with Ar2 or when A1=A2-A3=A4 is a radical of formula (a-1) or (a-2), R6 may also be 1H-benzimidazol-2-yl;
R7 is C1-6alkyl, Ar2-C1-6alkyl, Ar2, amino, Ar2-amino, mono-and di(C1-6alkyl)amino, mono- and di(Ar2-C1-6alkyl)amino, 1-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, C3-6cycloalkyloxy, C1-6alkyloxy or Ar1-C1-6alkyloxy;
Z is O, NR8 or a direct bond: said R8 being hydrogen or C1-6alkyl optionally substituted with Ar1;
R9 is Ar3;
each Alk independently being C1-6alkanediyl;
Ar1 is phenyl, substituted phenyl, napthalenyl, thienyl, halothienyl, C1-6alkyl substituted thienyl or furanyl, wherein said substituted phenyl is phenyl substituted with 1, 2 or 3 substituents, each independently selected from the group consisting of halo, hydroxy, nitro, cyano, trifluoromethyl, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, mercapto, C1-6alkylsulfonyl, C1-6alkylsulfonylC1-6alkyl, phenyl-C1-6alkylsulfonyl, phenylsulfonylC1-6alkyl, amino, mono- and di(C1-6alkyl)amino, carboxyl, C1-6alkyloxycarbonyl and C1-6alkylcarbonyl;
Ar2 has the same meanings of Ar1, and may also be pyridinyl, mono-and di(C1-6alkyloxy)pyridinyl or furanyl substituted with C1-6alkyl; and Ar3 has the same meanings of Ar2, and may also be pyrazinyl, 1-(C1-6alkyl)pyrrolyl, thiazolyl or imidazolyl optionally substituted with C1-6alkyl;
provided that A1=A2-A3=A4 is a radical of formula (a-1) or (a-2) when L is a radical of formula (b-4).

2. A chemical compound according to claim 1 wherein R is hydrogen, R1 is furanyl substituted with C1-6alkyl and R2 is hydrogen or C1-4alkyl.

3. A chemical compound according to claim 2 wherein L is C3-6alkenyl optionally substituted with phenyl or substituted phenyl, or wherein L is a radical of formula (b-1), (b-2), (b-4) or (b-5) wherein R4 is C1-6alkyl, phenyl or substituted phenyl, R7 is phenyl, substituted phenyl or C1-6alkyl optionally substituted with phenyl or substituted phenyl, R8 is hydrogen or C1-6alkyl, and R9 is phenyl, substituted phenyl or naphthalenyl.

4. A chemical compound according to claim 3 wherein L is a radical of formula (b-1) or (b-2) wherein R3 is hydrogen, phenylsulfonyl, 4,5-dihydro-5-oxo-1H-tetrazol-1-yl being optionally substituted in its 4-position with C1-4alkyl, 2,3-dihydro-1,4-benzodioxin-2-yl, 4-morpholinyl, 1-piperidinyl or 1-pyrrolidinyl, or when R1 is furanyl substituted with C1-6alkyl and A1-A2-A3=A4 is a bivalent radical of formula (a-1) or (a-2), R3 may also be 2,3-dyhydro-2-oxo-1H-benzimidazol-1-yl, thienyl, furanyl, phenyl or substituted phenyl.

5. A chemical compound according to claim 4 wherein -Alk-R1 is C1-4alkyl-5-C1-4alkyl-2-furanyl, C1-4alkyl-4-C1-4alkyl-2-furanyl, C1-4alkyl-3-C1-4alkyl-2-furanyl, C1-4alkyl-2-C1-4alkyl-3-furanyl, C1-4alkyl-4-C1-4alkyl-3-furanyl or Cl-4alkyl-5-C1-4alkyl-3-furanyl.

6. A chemical compound according to claim 5 wherein A1=A2-A3=A4 is a bivalent radical of formula (a-1) or (a-2) and L is a radical of formula (b-1) wherein R3 is hydrogen or phenyl optionally substituted with halo, C1-4alkyl, C1-4alkyloxy or hydroxy.

7. A chemical compound according to claim 1 wherein the compound is 3-[(5-methyl-2-furanyl)methyl]-N-(1-methyl-4-piperidinyl)-3H-imidazo-[4,5-b]pyridin-2-amine.

8. An anti-allergic composition comprising one or more pharmaceutical carriers and as active ingredient an anti-allergic effective amount of at least one compound of formula (I) as claimed in claim 1.

9. An anti-allergic composition according to claim 8 wherein R is hydrogen, R1 is furanyl substituted with C1-6alkyl and R2 is hydrogen or C1-4alkyl.

10. An anti-allergic composition according to claim 9 L is C3-6alkenyl optionally substituted with phenyl or substituted phenyl, or wherein L is a radical of formula (b-1), (b-2), (b-4) or (b-5) wherein R4 is C1-6alkyl, phenyl or substituted phenyl, R7 is phenyl, substituted phenyl or C1-6alkyl optionally substituted with phenyl or substituted phenyl, R8 is hydrogen or C1-6alkyl, and R9 is phenyl, substituted phenyl or naphthalenyl.

11. An anti-allergic composition according to claim 10 wherein L is a radical of formula (b-1) or (b-2) wherein R3 is hydrogen, phenylsulfonyl, 4,5 dihydro-5-oxo-1H-tetrazol-1-yl being optionally substituted in its 4-position with C1-4alkyl, 2,3-dihydro-1,4-benzodioxin-2-yl, 4-morpholinyl, 1-piperidinyl or 1-pyrrolidinyl, or when R1 is furanyl substituted with C1-6alkyl and A1=A2-A3=A4 is a bivalent radical of formula (a-1) or (a-2), R3 may also be 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl, thienyl, furanyl, phenyl or substituted phenyl.

12. An anti-allergic composition according to claim 11 wherein A1=A2-A3=A4 is a bivalent radical of formula (a-1) or (a-2) and L is a radical of formula (b-1) wherein R3 is hydrogen or phenyl optionally substituted with halo, C1-4alkyl, C1-4alkyloxy or hydroxy.

13. An anti-allergic composition according to claim 8 wherein the compound is 3-[(5-methyl-2-furanyl)methyl]-N-(1-methyl-4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine.

14. A use of an effective anti-allergic amount of a compound of formula (I) as claimed in claim 1 for treating allergic diseases in warm-blooded animalssuffering from the same.

15. A use according to claim 14 wherein R is hydrogen, R1 is furanyl substituted with C1-6alkyl and R2 is hydrogen or C1-4alkyl.

16. A use according to claim 15 wherein L is C3-6alkenyl optionally substituted with phenyl or substituted phenyl, or wherein L
is a radical of formula (b-1), (b-2), (b-4) or (b-5) wherein R4 is C1-6alkyl, phenyl or substituted phenyl, R7 is phenyl, substituted phenyl or C1-6alkyl optionally substituted with phenyl or substituted phenyl, R8 is hydrogen or C1-6alkyl, and R9 is phenyl, substituted phenyl or naphthalenyl.

17. A use according to claim 16 wherein L is a radical of formula (b-1) or (b-2) wherein R3 is hydrogen, phenylsulfonyl, 4,5-dihydro-5-oxo-1H-tetrazol-1-yl being optionally substituted is its 4-position with C1-4alkyl, 2,3-dihydro-1,4-benzodioxin-2-yl, 4-morpholinyl, 1-piperidinyl or 1-pyrrolidinyl, or when R1 is furanyl substituted with C1-6alkyl and A1=A2-A3=A4 is a bivalent radical of formula (a-1) or (a-2), R3 may also be 2,3-dihydro-2-oxo-1H-benzimi-dazol-1-yl, thienyl, furanyl, phenyl or substituted phenyl.

18. A use according to claim 17 wherein A1=A2-A3=A4 is a bivalent radical of formula (a-1) or (a-2) and L is a radical of formula (b-1) wherein R3 is hydrogen or phenyl optionally substituted with halo, C1-4alkyl, C1-4alkyloxy or hydroxy.

19. A use according to claim 14 wherein the compound is 3-[(5-methyl-2-furanyl)methyl]-N-(1-methyl-4-piperidinyl)-3H-imidazo[4,5-b]-pyridin-2-amine.

20. A process for preparing a compound of formula (I)as claimed in claim 1 characterized by I. a) N-alkylating a piperidine of formula H-D (II) with a reagent of formula L-W1 (III), wherein D represents a radical of formula wherein A1=A2-A3=A4, R, R1 and R2 have the previously described meanings; and wherein W1 represents a reactive leaving group, in a reaction-inert solvent;
b) reductively N-alkylating a piperidine of formula H-D (II) with a ketone or aldehyde of formula L1=0 (IV), said L1=0 being an intermediate of formula L1H2 wherein two geminal hydrogen atoms are replaced by =0, in a reaction-inert solvent, thus preparing a compound of formula L1H-D (I-a), wherein L1 is a geminal bivalent radical comprising R3 -C1-6alkylidene, R4 -0-C1-6alkylidene, R6R5-N-C1-6alkyldene and R7-C(=0)-Z-C1-6alkylidene;

c) O-alkylating an intermediate of formula HO-Alk-D (V) with a reagent of formula R4-a-W1 (VI) wherein R4-a is Ar1, in a reaction-inert solvent, thus preparing a compound of formula R4-a-O-Alk-D (I-b):

d) O-alkylating an intermediate of formula W1-Alk-D (VII) with a reagent of formula R4-a-O-H (VIII) wherein R4-a is Ar1, in a reaction-inert solvent, thus preparing a compound of formula (I-b);

e) reacting an isocyanate of formula R7-a-N=C=O (X) wherein R7-a-NH- is amino, Ar2-amino, C1-6alkylamino or Ar2-C1-6alkylamino, with an intermediate of formula H-Z1-Alk-D (IX) wherein Z1 is NR8 or O, in a reaction-inert solvent, thus preparing a compound of formula R7-a-NH-C(=0)-Z1-Alk-D (I-c-1);

f) reacting a reagent of formula R7-b-H (XII) wherein R7-b has the meaning of R7 as defined in claim 1 provided that it is other than Ar2 or C1-6alkyl optionally substituted with Ar2, with an isocyanate of formula O=C=N-Alk-D (XI) in a reaction-inert solvent, thus preparing a compound of formula R7-b-C(=0)-NH-Alk-D (I-c-2);

g) reacting a reagent of formula R7-c-C(=O)-OH (XIII), wherein R7-c is Ar2 or C1-6alkyl optionally substituted with Ar2, with (IX), in a reaction-inert solvent, if desired, after converting the OH group in (XIII) in a reactive leaving group or by reacting (XIII) with (IX) in the presence of a reagent capable of forming esters or amides, thus preparing a compound of formula R7-c-C(=O)-Z1-Alk-D (I-c-3);

h) reacting an alkenylene of formula L2-C2-6alkenediyl-H (XIV), wherein L2 being Ar1-thio, Ar3-sulfonyl, Ar2, C1-6alkylcarbonyl, Ar2-C1-6alkylcarbonyl, Ar2-carbonyl, C1-6alkyloxycarbonyl, Ar1-C1-6alkyloxycarbonyl or C3-6cycloalkyloxycarbonyl, with a piperidine of formula H-D (II), in a reaction-inert solvent, thus preparing a compound of formula L2-C2-6alkanediyl-D (I-d);

i) reacting a reagent of formula , with a piperidine of formula H-D (II), in a reaction-inert solvent, thus preparing a compound of formula R9-O-CH2-CH(OH)-CH2-D (I-e);

j) reducing an intermediate of formula C1-6alkyl-O-C(=O)-D (XVI) with a reductant such as lithium tetrahydroaluminate in a reaction-inert solvent, thus preparing a compound of formula CH3-D (I-f); or II. N-alkylating an intermediate of formula (XVII) with a reagent of formula W-Alk-R1 (XVIII) in a reaction-inert solvent; or III. cyclodesulfurizing an intermediate of formula (XIX) which may in situ be prepared by condensing an isothiocyanate of formula (XX) with a diamine of formula (XXI), with an alkylhalide, metal oxide or metal salt in a reaction-inert solvent; or IV. reacting a piperidine of formula (XXII) with a benzimidazole derivative of formula (XXIII) in a reaction-inert solvent wherein in (XXII) and (XXIII) either Q1 is -NHR2 and Q2 is W, or Q1 is W1 and Q2 is -NHR2 W and W1 represent an appropriate leaving group such as, for example, halo, preferably, chloro, bromo or iodo, or a sulfonyloxy group such as, for example, methylsulfonyloxy or 4-methylphenylsulfonyloxy, whereas W may also be C1-6alkyloxy and C1-6alkylthio, or Q1 is =0 and Q2 is NHR2; or optionally converting the compound of formula (I) into each other following art-known grouptransformation procedures, and, if desired, converting the compounds of formula (I) into a therapeutically active non-toxic acid-addition salt form by treatment with an appropriate acid or, conversely, converting the acid-addition salt into tha free base form with alkali; and/or preparing stereochemically isomeric forms thereof.